Methods and devices for sterilizing and holding buffering solution cartridges

ABSTRACT

Trays comprising a base have a plurality of axial slots adapted to receive buffer or other medical solution containers within the slots. A spring or other compression element at the bottom of the slot is configured to engage a plunger at the bottom of the solution container when present in the slot so that pressure is applied to the contents of the container in order to stabilize the contents while the containers are sterilized at an elevated temperature.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/833,356 (now U.S. Pat. No. 8,585,963), filed Jul. 9, 2010, whichclaims the benefit of the following prior provisional application Nos.61/270,571, filed on Jul. 9, 2009; 61/270,572, filed on Jul. 9, 2009;and 61/276,137, filed on Sep. 8, 2009, the full disclosures of which areincorporated herein by reference; U.S. patent application Ser. No.12/833,356 (now U.S. Pat. No. 8,585,963), filed Jul. 9, 2010, is also acontinuation-in-part of co pending application Ser. No. 12/766,259,filed on Apr. 23, 2010, the full disclosure of which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to methods and apparatus forsterilizing medical buffers and other solutions. More specifically, thepresent invention relates to methods and devices for holding medicalbuffers and solutions under pressure while undergoing heatsterilization.

A buffer solution is a solution that tends to change the pH of othersolutions with which it comes in contact to the buffer solution's pH.Medical buffer solutions frequently contain bicarbonate ions and areused in numerous medical applications including antidotes, dialysates,body replacement fluids, body irrigating solutions, cardiac perfusates,and for many other purposes. One of the most commonly used medicalbicarbonate buffer solutions consists of sodium bicarbonate (NaHCO₃)mixed with water, which among other things, can be used to bufferparenteral injections to a more physiologic pH prior to injection. Ofparticular interest to the present application, bicarbonate solutionsmay be used to buffer acidic local anesthetic injections in order toenhance anesthetic effectiveness, reduce injection pain, and limittissue trauma. For use of sodium bicarbonate for buffering localanesthetic, as well as for other medical uses including but not limitedto treatment of acidosis, it is desirable that sodium bicarbonatesolutions be precisely maintained at or near a particular known pH.Using a buffer solution having a known pH allows a medical practitionerto mix a predetermined ratio of the buffer solution with the parenteralsolution in order to achieve control over the resulting pH of parenteralsolution, which has significant benefits over using a parenteralsolution where the pH is not controlled.

As an example, when compounding 8.4% sodium bicarbonate buffer solutionwith commercially available cartridges of 2% lidocaine with epinephrine1:100,000, the pH of the buffer solution will tend to drive the pH ofthe combination, almost exclusively of the pH of the commerciallyavailable anesthetic cartridges, such that a relatively small volume ofbuffer solution will have a disproportionately large impact on the pH ofthe combined solution. Thus, to achieve a parenteral solution with apredictable pH, it is important that the pH of the buffer solution beprecisely known and controlled, in addition to knowing and controllingthe amount of buffering solution to add to the local anesthetic. Onlywhen the pH of the buffer solution being added and the amount of bufferbeing added are both known can the practitioner know and control theresulting pH of the buffered anesthetic.

Commercially produced sodium bicarbonate buffers do not provide bufferpackages with precisely controlled pH. For example, an assay of thecommercially available sodium bicarbonate solutions performed by theinventors showed a pH range from 7.62 to 8.26 in a number ofcommercially obtained bicarbonate buffer cartridges. Presumably theactual range of the product available in the marketplace is even widerthan the range identified in this small assay.

It must be appreciated, in this context, that a medical buffer having anactual pH of 7.6 may perform significantly differently than a medicalbuffer having an actual pH of 8.3. This is true whether the medicalbuffer is designed to buffer the pH of the body's fluids, for instancein the treatment of acidosis, or the medical buffer is designed tobuffer the pH of a parenteral solution prior to its use. In the examplewhere a practitioner uses sodium bicarbonate solution to bufferanesthetic to achieve physiologic pH, the ratio of buffer solution toanesthetic solution will be quite different when the pH of thebicarbonate solution is 7.6 compared to when the pH is 8.3. Thus, priorart methods of combining buffering solution with parenteral solutionswhich rely on adding the same ratio of buffering solution to theparenteral solution, regardless of the actual pH of the buffer, will notconsistently arrive at a desired pH for the buffered parenteral.

A method and system for adjusting the pH of medical buffers and othermedical solutions to a precisely controlled value in a plurality ofidentical buffer cartridges or other containers is described in copending application Ser. No. 12/766,259, filed on Apr. 23, 2010, thefull disclosure of which is incorporated herein by reference. Thatapplication teaches that the pH of the solutions in individualcontainers can be adjusted by exposing those containers, while open, toan environment having a controlled temperature, humidity, pressure, andlevel of carbon dioxide. After the pH has equilibrated to a target pH,the cartridges can be sealed with no head space remaining within thecartridges. Once the cartridges are sealed, an inventory of cartridgeshaving precisely controlled and identical pH values can be created. Theneed to sterilize the containers and their contents, however, canadversely affect the contents of the cartridges. Sterilization istypically done at elevated temperatures which can cause the buffer orother medical solution to boil, which can cause the seals to fail or canotherwise adversely impact the solution and the container.

For these reasons, it would be desirable to provide methods andapparatus for sterilizing cartridges and similarly packaged buffersolutions so as to prevent boiling and other adverse changes that mightoccur during heat sterilization. It would be particularly desirable tobe able to sterilize multiple buffer or other medical solution packagessimultaneously while holding the packages in trays or other containersthat are also suitable for subsequent storage and shipment of thebuffers. At least some of these objectives will be met by the inventionsdescribed hereinbelow.

2. Description of the Background Art

Glass vials and cartridges for storing medical solutions are describedin U.S. Pat. Nos. 1,757,809; 2,484,657; 4,259,956; 5,062,832; 5,137,528;5,149,320; 5,226,901; 5,330,426; and 6,022,337. Injection pens whichemploy drug cartridges are described in U.S. Pat. No. 5,984,906.Exemplary disposable drug cartridge that could be loaded with buffersolution in accordance with the present invention are described in U.S.Pat. No. 5,603,695 and in commonly owned, co pending applicationUS2009/0292271 (U.S. Ser. No. 12/406,670), both of which areincorporated herein by reference. A device for delivering a bufferingagent into an anesthetic cartridge using a transfer needle is describedin U.S. Pat. No. 5,603,695. Devices for maintaining a dissolved gas insolution in a pouch are described in U.S. Pat. Nos. 5,690,215;5,610,170; and 4,513,015, and U.S. Patent Publ. No. 2007/0265593. Otherpatents and applications of interest include U.S. Pat. Nos. 2,604,095;3,993,791; 4,154,820; 4,630,727; 4,654,204; 4,756,838; 4,959,175;5,296,242; 5,383,324; 5,603,695; 5,609,838; 5,779,357; and U.S. PatentPubl. No. 2004/0175437. Literature publications describing bufferinganesthetics with widely different ratios of a sodium bicarbonatesolutions include Ridenauer et al., Anesth Prog, vol. 48, p. 9-15(2000); Palmon et al., Anesth Analg, vol. 86, pp. 379-81 (1998);Metzinger et al., Southern Med J, vol. 87, no. 2 (1994); Nelson,Contracept, vol. 55, p. 299 (1995); Samdal, Scand J Plast and ReconsSurg and Hand Surg, vol. 28, p. 33-37 (1993); Master, Br. J Plast Surg,vol. 51, p. 385 (1998); Difazio et al. Anesth Analg, vol. 65, p. 760(1986); Fitton et al., Br. J Plast Surg, vol. 49, pp. 404-08 (1996);Peterfreund et al., Region Anesth, vol. 14, no. 6, p. 265 (1989); Momsenet al., Ugeskr Laeger, vol. 162, no. 33, p. 4391 (2000); Schwab et al.Am J Emerg Med, vol. no. 3 (1996); McGlone et al. Arch Emerg Med, vol.7, pp. 65-68 (1990); and Sapin P, et al. Catheterization and CardioDiag, vol. 23, pp. 100-102 (1991).

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods and apparatus for sterilizing,transporting, and storing medical solution containers, such ascartridges and carpules, which hold injectable medical solutions, suchas buffer solutions. Buffers and other medical solutions are oftenlabile and at risk of boiling at the elevated temperatures used insterilization. In particular, sodium bicarbonate buffer solutions aresubject to the evolution out of solution of carbon dioxide (CO₂), whichcan affect the pH of the buffer if all of the liberated CO₂ does notreturn to solution upon cooling. While the following disclosure isdirected particularly at methods and apparatus for sterilizing sodiumbicarbonate buffers and other medical solutions having salts with areversible equilibrium at near saturation, the invention extends to anymedical solution held in a container or carpule which is subject toboiling or partial vaporization when sterilized in the cartridge atelevated temperatures.

The present invention is particularly intended for sterilizing andstoring small medical cartridges, sometimes referred to as carpules,comprising a small glass or plastic vial having a needle-penetrableseptum at a top end and a displaceable plunger at a bottom end thereof.Such cartridges can be placed in a syringe or other delivery systemwhere a needle penetrates the septum to access the buffer or othercontents and a shaft of the system advances the plunger to deliver thesolution through the needle. A dosing pen system useful for bufferinganesthetic cartridges with buffers prepared by the present invention isdescribed in co pending application Ser. No. 12/406,670, filed on Mar.18, 2009, the full disclosure of which is incorporated herein byreference.

Medical bicarbonate buffer solutions are buffers that rely on thecombination of carbon dioxide (CO₂) with water to form carbonic acid(H₂CO₃) which dissociates to a hydrogen ion (H⁺) and a bicarbonate ion(HCO₃ ⁻). In using such bicarbonate solutions to buffer medicalsolutions, including local anesthetics such as lidocaine, articaine,prilocaine, and mepivacaine, both the amount of the bicarbonate solutionand the pH of the bicarbonate solution used and the pH of thebicarbonate solution used are determinative of the pH of the medicalsolutions after the two solutions have been combined. Vieweddifferently, the amount of buffering solution needed to stabilize amedical solution at a particular target pH will depend on the pH of thebuffering solution itself. Thus, a measured volume of buffering solutioncannot be relied on to adjust the pH of a medical solution toward atarget pH when the actual pH of the buffering solution variessignificantly from its nominal pH, which would cause the stabilized pHof the buffered medical solution to differ significantly from the targetvalue. Thus, any uncertainty or change in the pH of the bufferingsolution resulting from sterilization of the cartridge of bufferingsolution can significantly affect the pH of the anesthetic when combinedwith the buffer, making it very difficult for the physician to preciselycontrol the buffered pH of the anesthetic delivered to a patient.

The present invention provides methods and apparatus which can stabilizethe pH of the buffer or other medical solution sealed in a cartridgeduring heat sterilization. In particular, the present invention providesmethods and holding or storage trays which can apply external pressure(above atmospheric pressure) to the medical solution within thecontainer in order to raise the pressure of the solution to a levelsufficient to inhibit or prevent boiling during the sterilization. Whilein some cases where boiling of the bicarbonate solution is prevented,some bubbles of carbon dioxide may temporarily initiate or form, thepresent invention will prevent irreversible carbon dioxide bubbleformation, or formation of bubbles that do not return to solution duringcooling of the solution after head sterilization. By applying thepressure and preventing the irreversible bubble formation, it has beenfound that deleterious changes in the pH of the medical solution can beprevented.

Surprisingly, the inventors have further discovered that applying apressure which is too high (above an upper threshold or limit) canresult in irreversible crystallization of salts in the buffer or othermedical solution, which can make the solution unusable. In the case ofthe exemplary sodium bicarbonate buffers of the present invention,pressures applied above an upper threshold has been found to cause thebuffer salt to crystallize in an irreversible manner, thus becoming aprecipitate that makes the solution unsuitable for buffering parenteralsolutions, and for many other medical purposes.

In a first aspect of the present invention, sealed containers filledwith medical solutions are heat sterilized in a manner where a force isapplied to the solution in the container, for instance by placing aforce against a rubber stopper or plunge in a cartridge filled with themedical solution. The container is exposed to an elevated temperaturesufficient to sterilize the container and the medical solution. Theforce applied to the stopper is sufficient to create pressure in thesolution that inhibits boiling the water contained in the medicalsolution, as well as being sufficient to inhibit the evolution of vaporsother than water out of solution (for instance carbon dioxide gas). By“sufficient to inhibit the evolution of vapors other than water out ofsolution,” it is meant that the pressure will prevent the irreversibleformation of such vapor bubbles within the solution while the solutionis being held at the elevated sterilization temperature. In some cases,small vapor bubbles may transiently be produced, but such vapor bubbleswill quickly disappear upon cooling, and the generation of such smallvapor bubbles will not adversely affect the pH or other desirablecharacteristic of the medical solution. The external pressure thatprevents this vapor formation must not be so high as to prevent thermalexpansion of the fluid, which could cause the container or its seals tofail. Also significantly, the external pressure must be kept below anupper limit at which, if the pressure of the solution exceeds the limit,crystallization of the buffer or other species in the medical solutioncan occur.

The methods are particularly useful for sterilizing medical buffers,more particularly for sterilizing sodium bicarbonate buffers. For suchbicarbonate buffers, the sterilization temperature is usually in therange from 100° C. to 140° C. and the internal pressure before, during,and after heat sterilization will being in the range from 0.7 kPa (14.7psig) to 8.3 kPa (175 psig). The containers that are held under pressurein this range are usually exposed to the elevated temperature of a heatsterilizer for a duration that ranges from 3 minutes to 60 minutes,where longer times generally are used at lower sterilizationtemperatures.

In specific embodiments, the containers being sterilized will becartridges that have an open interior filled with the medical solution,a needle-penetrable septum, and a plunger. The pressure on the solutionmay be applied by engaging a compression member, such as a coil or otherspring, against the plunger. In some embodiments, the containers areheld in a tray having a plurality of springs or other compressionmembers arranged to engage the plungers to apply the pressure when saidcontainers are placed in the tray. Usually, the tray includes aplurality of slots with the springs at one end of the slot. A retaineris typically used to hold a top of the container within the slot inorder to push or compress the plunger within the container with adesired force (depending on the spring constant, degree to which thespring has been compressed, and the area of the plunger) sufficient toachieve the desired elevated pressure prior to and after the steamsterilization process. During the sterilization process itself, thecharacteristics of the spring must be such that the spring can absorbthe thermal expansion of the fluid without which absorption, thecontainer may shatter. Significantly, the spring must also be softenough to absorb the thermal expansion of the solution and prevent theexpansion

In a second aspect of the present invention, a tray comprises a basehaving a plurality of aligned slots. Each slot is arranged to receive acontainer which holds a medical solution, such as a buffer. Thecompression member, such as a spring, is disposed at the bottom of eachslot and is oriented to engage a plunger on a bottom of the medicalsolution container when the container is held within the slot. Retainersare disposed at the top of each slot and positioned to engage a top ofthe container to position the container axially within the slot so thatthe plunger on the container is held against the compression member atthe bottom of the slot with a force (determined by the degree ofcompression of the spring or other compression member) sufficient toraise the pressure of the medical solution to a level which inhibits theevolution of vapor within the solution when the container is exposed toan elevated temperature sufficient to sterilize the solution.

The trays will typically be used to sterilize the containers as well asto ship and to store the containers. Thus, the present invention furthercomprises the trays having a plurality of containers therein, where thecontainers each contain a medical solution which has been sterilizedwhile held within the tray. Typically, the medical solutions in each ofthe containers will be identical with identical characteristics. Forexample, the containers may each contain a sodium bicarbonate bufferhaving at or near identical pH and other characteristics within each ofthe containers.

When the tray is intended to hold containers with medical buffers,particularly sodium bicarbonate buffers, the compression member will beconfigured to raise the pressure to at least 0.7 kPa (14.7 psig) whenthe container is held within the slot, typically raising the pressure toa value in the range from 0.7 kPa to 8.3 kPa (175 psig) during heatsterilization. In the exemplary embodiments, the compression members areaxially compressible springs, typically coil springs, with a springconstant in the range from 1.1 Nm to 11 Nm, and wherein the retainer ispositioned to compress the spring by a distance in the range from 0.5 mmto 5 mm when the plunger has an area of 20 mm².

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a sterilization and storage trayconstructed in accordance with the principles of the present invention.

FIG. 2 is a front view of the storage and sterilization tray of FIG. 1shown with one container removed, one container partially inserted intoa slot, and two containers fully inserted into their slots.

FIG. 3 illustrates a method for preparing pH-stabilized buffercartridges by placing uncapped cartridges in a carrier that is placed inan pH equilibration chamber.

FIG. 4 illustrates a plurality of storage and sterilization trays beingsterilized in an autoclave in accordance with the principles of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

Referring to FIGS. 1 and 2, a storage and sterilization tray 80constructed in accordance with the principles of the present inventioncomprises a base 84 defining a plurality of axial slots 86, where eachslot has a compression member, such as coil spring 82 at a bottom endand a removable retainer 90 at an upper end. The retainers 90 areremovably received in openings 92 at the top of each axial slot, as bestseen in FIG. 2. Single containers 10 are received in each slot 86 bypassing the container downwardly through the opening 92 so that amovable plunger 24 at the bottom of the container engages the spring 82,as seen in FIG. 2. In particular, the cartridge 10 is inserted into theaxial slot 86 so that the plunger 24 first engages a top 83 of thespring and then partially compresses the spring as shown in the twomiddle slots of the tray 80. Once the cartridge 10 is fully inserted,the retainer 90 can be replaced in the opening 92 to properly maintainthe position of the cartridge so that the spring remains compressed toapply the desired compression force against the contents of thecartridge 24, as shown in the two right-hand slots of tray 80 in FIG. 2.The spring will not be fully compressed, thereby allowing thermalexpansion to occur during heat sterilization such that the thermalexpansion does not create sufficient pressure to either burst thecontainer or cause crystallization of components of the solution.

Referring now to FIG. 3, the trays 80 are particularly useful forsterilizing buffer cartridges 10 which have been filled with bicarbonatebuffer which is then stabilized to an accurate and repeatable pH, asdescribed in greater detail in co pending application Ser. No.12/766,259, the full disclosure of which has been previouslyincorporated herein by reference. Initially, the individual buffercontainers 10 are filled with the aqueous bicarbonate buffer B toappoint near meniscus M. Usually, the volume of buffer B introduced willbe selected so that the upper surface or meniscus M of the buffer liesbelow the reduced diameter neck 16 so that the meniscus M has a largerarea than it would have if it were present within the neck. This largerarea allows the carbonic acid within the buffer to reach equilibriumwith the carbon dioxide in the atmosphere within the chamber 40 morerapidly than if the area were reduced. The containers 10 are thenintroduced to the treatment chamber 40, typically after placement oncarriers. After the containers 10 have been loaded onto the supports 50,they are left to equilibrate with the carbon dioxide environment whichis continuously being replenished with the carbon dioxide gas for anumber of hours under the conditions described above. After a sufficienttime has passed for the buffer within the containers to equilibrate withthe carbon dioxide within the treatment chamber 40, the containers areremoved and the plungers 24 advanced to raise the level of buffer to theopening 18 in the neck 16. Caps 20 are then placed over the necks 16,leaving little or no head space, and the individual sealed containers 10then placed in a storage tray 80 where springs 82 can be engaged againstthe plungers 24 to pressurize the buffers to inhibit the evolution ofcarbon dioxide gas from the buffer solution. By limiting such evolution,the pH of the buffer will be more stably maintained. The treatment trays80 are also suitable for autoclaving the containers to assure sterilityas described below. The containers may then be stored and distributedwithin the trays 80 or may be stored and distributed in separatecontainers.

Referring to FIG. 4, sterilization can be performed in an autoclave 100which is designed to expose the trays 80 and the cartridges 10 thereinto superheated steam at a temperature in the range from 100° C. to 150°C. The autoclave typically takes water, passes the water through aheater 102 which releases steam into the chamber of the autoclave 100.Steam and/or condensed water can be removed through upper or lowervalves 104 to maintain the desired pressure, if any, and temperaturewithin the autoclave 100. Suitable autoclaves are available from manycommercial suppliers, such as the AMSCO Eagle Model 3000 SL Sterilizer,commercially available from Steris Corp., Mentor, Ohio 44060. The trays80 are usually stacked on shelves 106 within the autoclave 100 and areheld at the elevated temperature and pressure for sterilization times asdescribed previously in this application. At all times, the springs 82will be applying an elevated pressure, again within the ranges set forthabove, to the buffer or other medical solutions within the containers inorder to inhibit vaporization but allow for thermal expansion withoutcreating crystallization. After the treatment time, the steam to theautoclave will be turned off and the temperature will return to ambient.When the trays 80 are removed from the autoclave 100, the buffer orother medical solution within the individual containers 10 will havebeen pH stabilized. Usually, the cartridges 10 may be maintained forstorage, shipment, and inventory within the trays 80, further reducingthe risk of damage or degradation to the containers or the medicalsolution contents.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. Therefore, the above description should not be taken aslimiting the scope of the invention which is defined by the appendedclaims.

What is claimed is:
 1. A method for sterilizing a container filled witha medical solution comprising a buffer, which solution evolves vaporwhen heated, said method comprising: providing a sealed container havingan open interior filled with the medical solution, a needle-penetrableseptum, and a plunger; applying a pressure above atmospheric pressure tothe medical solution within the sealed container by engaging acompression member against the plunger; and exposing the container to anelevated temperature sufficient to sterilize the medical solution withinthe container, wherein said temperature is sufficient to evolve thevapor at atmospheric pressure, and the applied pressure is sufficient toinhibit the evolution of the vapor within the container withoutprecipitating the buffer.
 2. A method as in claim 1, wherein the appliedpressure allows for thermal expansion of the solution duringsterilization, such that the solution does not achieve a pressuresufficient to cause the transformation of components of the solution tosolid form.
 3. A method as in claim 1, wherein the buffer is sodiumbicarbonate, the sterilization temperature is in the range from 100° C.to 150° C., and the pressure applied to the solution before, during, andafter autoclaving is at least 0.7 kPa (14.7 psig) but not more than 8.3kPa (175 psig).
 4. A method as in claim 3, wherein the container isexposed to the elevated temperature and the applied pressure for a timein the range from 3 minutes to 60 minutes.
 5. A method as in claim 1,wherein a plurality of containers are held in a tray having a pluralityof compression members arranged to engage the plungers to apply saidpressure.
 6. A method as in claim 5, wherein the applied pressure allowsfor thermal expansion of the solution during sterilization, such thatthe solution does not achieve a pressure sufficient to cause thetransformation of the components of the solution to solid form.
 7. Amethod as in claim 2, wherein the buffer is sodium bicarbonate, thesterilization temperature is in the range from 100° C. to 150° C., andthe pressure applied to the solution before, during, and afterautoclaving is a least 0.7 kPa (14.7 psig) but not more than 8.3 kPa(175 psig).
 8. A method as in claim 7, wherein the container is exposedto the elevated temperature and the applied pressure for a time in therange from 3 minutes to 60 minutes.